Though agriculture is often viewed as one of humanity's crowning achievements, skeletal evidence indicates that dependence on domesticated plants and animals was accompanied by an increase in infectious disease. Scientists have proposed that many important infections emerged in the period following the advent of agriculture, as a result of newly dense populations and novel proximity to domestic animals that served as reservoirs for novel pathogens. Here, we review genomic evidence regarding pathogen origins, analyzing these data using the epidemiological transition framework. Genetic information has forced us to reconsider how and when many important pathogens emerged; it appears that a number of infections thought to result from contact with domesticated animals arose much earlier than agriculture was adopted. We also consider the broader effect of agriculture upon the microbiome, exploring potential consequences for human health. We end by discussing the changes in the human microbe-scape we are likely to see in the future. Am J Phys Anthropol 57:135–152, 2013. © 2013 Wiley Periodicals, Inc.